Wound healing is an intricately regulated process broadly characterized by phases of inflammation, proliferation, and remodeling. Imbalances in any one of these phases can result in inadequate healing, scar formation, or in the development of chronic wounds, such as diabetic ulcers. Diabetic ulcers are responsible for the majority of lower extremity amputations in the world and are among the principal reasons for hospitalization of diabetic patients. These chronic wounds are debilitating, painful, and frequently never completely heal. Despite extensive research and product development to improve wound care, the clinical standard of care for these lesions has been largely unchanged for decades. Inter-alpha Inhibitor Proteins (IAIP) are naturally derived molecules that serve as a crucial component of the body's protective defenses in modulating host response to pathological insults. Currently, these proteins are being developed as a potent therapy to treat acute life threatening diseases such as systemic inflammatory response syndrome (SIRS), sepsis and Anthrax intoxication and infection in biodefense applications. IAIP have been described to play an important role not only in inflammation and angiogenesis but also in the wound healing process. Our recent investigations using genetically altered mice deficient in IAIP (bikunin knockout mice) revealed a dysregulated wound repair process due to disruption of extracellular matrix (ECM) reorganization. Additionally, we found that IAIP level is markedly decreased in the wound tissues of diabetic mice compared to non-diabetic controls suggesting impaired and depleted IAIP in the diabetic wound. IAIP consist of multiple subunit (heavy and light) chains uniquely linked by glycosaminoglycan. While the IAIP light chain (also called bikunin) inhibits various serine proteases, the heavy chains of IAIP form covalent complexes with hyaluronan to allow efficient binding to its receptors (such as CD44). The IAIP heavy chains also known to interact with matrix cellular proteins such as vitronectin, fibronectin and tenascin c to promote wound healing. In this proposal we would like to develop a novel topical IAIP formulation and obtain proof-of-concept of efficacy of a localized IAIP treatment approach in three different experimental models of wound healing using IAIP-deficient (KO), monogenetic diabetic and polygenetic TallyHo diabetic mice. We hypothesize that IAIP will play a significant role in the wound healing process affecting epidermal regeneration as well as extracellular matrix organization. If confirmed, this novel topical treatment based on plasma derived IAIP can be translated readily into the clinical use for problematic and chronic wound care. The localized immunomodulatory IAIP treatment might also prevent wound complication and super infection making the potential impact of this research immense.